The dopamine transporter is a presynaptically located macromolecule which plays an important role in pathophysiocological processes in the central nervous system (CNS). The DAT terminates dopaminergic neurotransmission by reaccumulation of released dopamine into presynaptic neurons, M. J. Kuhar, “Neurotransmitter Uptake: A Tool in Identifying Neurotransmitter Specific Pathways”, LIFE SCI., 13, 1623-34, 1973. In cocaine addiction, binding of cocaine to the DAT and consequent blockage of dopamine uptake appears to be related to the reinforcing properties of the drug. M. E. A. Reith et al., “Structural Requirements for Cocaine Congeners to Interact With Dopamine and Serotonin Uptake Sites in Mouse Brain and to Induced Stereotyped Behavior”, BIOCHEM. PHARMACOL., 1986, 35, 1123-1129; M. C. Ritz et al., “Cocaine Inhibition of Ligand Binding At Dopamine, Norpinephrine and Serotonin Transporters: A Structure-Activity Study”, LIFE. SCI., 1990, 46, 635-645; M. C. Ritz et al., “Cocaine Receptors On Dopamine Transporters Are Related to Self-Administration of Cocaine”, SCIENCE, 1987, 237, 1219-1223; B. Giros et al., “Hyperlocomotion and Indifference to Cocaine and Amphetamine in Mice Lacking the Dopamine Transporter”, NATURE, 1996, 379, 606-612. Also associated with the transport function is concentration of neurotoxic chemicals in dopaminergic neurons which is implicated in Parkinson's disease. The transporter macromolecule may be a marker for Parkinson's, H. Shoemaker et al., NAUNYN SCHMIEDEBERGS ARCH. PHARMACOL., 1985, 329, 227-235 and J.-M. Maloteaux et al., EUR. J. PHARM., 1988, 156, 331-340, as evidenced by its absence in tissue sections of Parkinson's diseased putamen. H. B. Niznik et al., ARCH. BIOCHEM. BIOPHYS., 1990, 276, 424-432 and M. J. Kaufman et al., SYNAPSE, 1991, 9, 43-49. Consequently, potent yet selective ligands for the DAT have potential for in vivo monitoring of primary targets of cocaine in the brain, for characterization of cocaine binding sites, for pharmacotherapeutic agents for treatment of cocaine addition, and for monitoring of Parkinson's Disease.
Cocaine is known to bind to various neurotransporter systems in the brain, M. E. A. Reith et al., op. cit., but the reinforcing effect of cocaine which is a factor in cocaine addition, is believed to be initiated by binding to the DAT, causing inhibition of dopamine transport. Phencyclidine (PCP), a psychoactive drug of abuse, is also known to exhibit at least some of its behavioral effects through binding to the DAT. K. M. Johnson, “Phencyclidine: Behavioral and Biochemical Evidence Supporting a Role For Dopamine”, FED. PROC., 1983, 42, 2579-2583; E. D. French et al., “Phencyclidine Binding Sites in the Nucleus Accumbens and Phencyclidine-Induced Hyperactivity are Decreased Following Lesions of the Mesolimbic Dopamine System”, EUR. J. PHARMACOL., 1985, 116, 1-9. The DAT further plays a crucial role in the neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which induces idiopathic Parkinson's syndrome in humans. J. Langston et al., MPTP: Current Concepts and Controversies”, CLIN. NEUROPHARMAC., 1986, 9, 485-507; H. Kinemuchi et al., “The Neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its Relevance to Parkinson's Disease”, NEUROCHEM. INT., 1987, 11, 359-373. The serotonin transporter (SERT) is also implicated in numerous neurological processes. For example, SERT is strongly implicated in depression and drug addiction.
Several classes of compounds have been developed to characterize cocaine and PCP binding sites at the DAT. M. E. A. Reith et al., op. cit., F. I. Carroll et al., “Cocaine Receptor: Biochemical Characterization and Structure-Activity Relationship of Cocaine Analogues at the Dopamine Transporter”, J. MED. CHEM., 1992, 35, 969-981; R. A. Millius et al., “Synthesis and Receptor Binding of N-substituted Tropane Derivatives”, “High Affinity Ligands For Cocaine Receptor”, J. MED. CHEM., 1991, 34, 1728-1731; I. Chaudieu et al., “Role of the Aromatic Group in the Inhibition of Phencyclidine Binding and Dopamine Uptake by PCP Analogs”, PHARMACOL. BIOCHEM. BEHAV., 1989, 32, 699-705. Extensive structure-activity relationship (SAR) studies of cocaine analogs resulted in the development of potent and selective tropane derivatives which bind to the DAT. Some well known compounds of this class include CFT (Win 35,428) and RTI-55. The similarity of the structures of these tropane derivatives and cocaine is readily apparent.

More recent reports describe yet more potent and selective tropanes, P. C. Meltzer et al., “Substituted 3-phenyltropane Analogs of Cocaine: Synthesis, Inhibition of Binding At Cocaine Recognition Sites, and Positron Emission Tomography Imaging”, J. MED. CHEM., 1993, 36, 855-862; F. I. Carroll et al., “Cocaine and 3β-(4′-substituted phenyl)tropane-2β-carboxylic acid ester and amide analogues. New High-affinity and Selective Compounds for the Dopamine Transporter”, J. MED. CHEM., 1995, 38, 379-388. In similar fashion, modification of PCP led to development of more potent analogs, I. Chaudieu et al., “Role of the Aromatic Group in the Inhibition of Phencyclidine Binding and Dopamine Uptake By PCP Analogs”, PHARMACOL. BIOCHEM. BEHAV., 1989, 32, 699-705; and J. Vignon et al., “[3H]N-[1-(2-Benzo(b)thienyl)cyclohexyl]piperidine([3H]BTCP): A New Phencyclidine Analog Selective for the Dopamine Uptake Complex”, EUR. J. PHARMACOL., 1988, 148, 427-436.

The “GBR” class of compounds, P. Van der Zee et al., “Aryl 1,4-dialk(en)ylpiperazines as Selective and Very Potent Inhibitors of Dopamine Uptake”, EUR. J. MED. CHEM, 1980, 15, 363-370, are known for their unusually high selectivity and potency for the DAT.

Two of these, with R═F and R═H, have affinities in the low nanomolar range. P. H. Anderson, “Biochemical and Pharmacological Characterization of [3H]GBR 12935 Binding in Vitro to Rat Striatal Membranes: Labeling of the Dopamine Uptake Complex”, J. NEUROCHEM., 1987, 48, 1887-1896; P. H. Anderson, “The Dopamine Uptake Inhibitor GBR 12909: Selectivity and Molecular Mechanism of Action”, EUR. J. PHARMACOL., 1989, 166, 493-504. An extensive structure/activity relationship (SAR) study produced several very potent compounds for the DAT. C. DeVries et al., “Heteroaromatic Analogs of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as High-Affinity Dopamine Reuptake Inhibitors”, J. MED. CHEM., 1997, 40, 705-716; D. Matecka et al., “Development of Novel, Potent, and Selective Dopamine Reuptake Inhibitors Through Alteration of the piperazine Ring of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909)”, J. MED. CHEM., 1996 39, 4704-4716. Radiolabeling of these compounds has facilitated elucidation of neuropharmacological activity. The GBR with R═F dissociates very slowly from the DAT, R. B. Rothman, “Tight Binding Dopamine Reuptake Inhibitors as Cocaine Antagonists”, FEBS LETT., 1989, 257, 341-344 and attenuates increase in extracellular dopamine levels induced by cocaine as measured by microdialysis. R. B. Rothman, op. cit.; U. Sogaard et al., “A Tolerance Study of Single and Multiple Dosing of the Selective Dopamine Uptake Inhibitor GBR 12909 in Healthy Subjects”, INT. CLIN. PSYCHOPHARM., 1990, 5, 237-251. This compound was non-stimulatory in human volunteers, J. R. Glowa et al., “The Effects of GBR 12909 on Responding of Rhesus Monkeys Maintained Under Schedules of Cocaine- and Food-Delivery”, NIDA. RES. MONOGR., 1994, 141, 12, and has recently been shown to block cocaine self-administration behavior in the rhesus monkey. A. K. Dutta et al., “Positional Importance of the Nitrogen Atom in Novel Piperidine Analogs of GBR 12909: Affinity and Selectivity for the Dopamine Transporter”, MED. CHEM. RES., 1993, 3, 209-222. Such studies raise the possibility that suitable compounds may serve as cocaine antagonists without being themselves addictive.